Is SCN5A p.Pro348= (c.1044C>T) pathogenic?

SCN5A p.Pro348= (c.1044C>T) is classified Conflicting classifications of pathogenicity in SCN5A (ClinVar, Conflicting submitters, 17 submitters; last evaluated 2026-01-25). Ultra-rare (popmax 0.0547%, nfe); Associated with cardiac rhythm disease.

What condition is associated with SCN5A p.Pro348= (c.1044C>T)?

SCN5A p.Pro348= (c.1044C>T) is associated with cardiac rhythm disease, progressive familial heart block, type 1A, Brugada syndrome 1 (ClinVar).

How common is SCN5A p.Pro348= (c.1044C>T) in the general population?

SCN5A p.Pro348= (c.1044C>T) is ultra-rare (popmax 0.0547%, nfe) (gnomAD).

SCN5A p.Pro348=

c.1044C>T · rs370346797 · VCV139044

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 17 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0547%, nfe)

Conditions

cardiac rhythm disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.7	GERP -4.2
Overall
CADD	4.509	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0547% European (non-Finnish) · 645/1,179,850 alleles

Filtering AF 0.0511% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0498%

Overall 0.0429% 692/1,613,854 alleles · ultra-rare exomes 629/1,461,494 · genomes 63/152,360 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0547%	1,829
African / African-American	0.0346%	2,887
Remaining individualsnot grpmax-eligible	0.0176%	5,680
Admixed American	0.0133%	7,504
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
Finnishnot grpmax-eligible	0.00157%	63,892

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: SCN5A
Protein: p.Pro348=
Coding: c.1044C>T
MANE Select: NM_000335
dbSNP: rs370346797
Type: single nucleotide variant
Location: chr3:38606765 (GRCh38)
Gene constraint: LOEUF 0.372 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.02 · 16 PDB

Full SCN5A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cardiac rhythm disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: progressive familial heart block, type 1A Brugada syndrome 1 dilated cardiomyopathy 1E ventricular fibrillation, paroxysmal familial, type 1 long QT syndrome 3 sick sinus syndrome 1

Similar variants

SCN5A c.1140+1G>A Pathogenic/Likely pathogenic ★★ same condition
SCN5A c.1338+2T>A Pathogenic/Likely pathogenic ★★ same condition
SCN5A c.2263-2A>G Likely pathogenic ★★ same condition
SCN5A c.2787+1G>T Likely pathogenic ★★ same condition
SCN5A c.3508+1G>T Likely pathogenic ★★ same condition
SCN5A c.3837+1G>A Pathogenic ★★ same condition
SCN5A c.4242+1G>C Pathogenic/Likely pathogenic ★★ same condition
SCN5A c.4296+1G>A Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/scn5a-p-pro348 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown